Currently, targeted therapies for cancer treatments are based on the identification of a specific protein contributing to tumor progression, and the identification of a specific agent that is capable of antagonizing the effect of the above proteins. The pharmaceutical industry mostly concentrates efforts on a very limited number of well-validated protein targets. Common defect lies in that the occurrences of drug-resistance mutations are often found in cancer patients treated with these specific inhibitors. Recently, a general view is that simultaneously blocking signaling pathways involving cancer progression may be expected to contribute to a better anti-tumor effect, and reduce the likelihood of drug-resistance development. HSP90 belongs to a small family of proteins that generally have a very specific C-mode (Bergerat fold) linked to adenosine triphosphate (GHKL, derived from DNA gyrase, HSP90, histidine kinase, mutL). HSP90 is one of the most abundant proteins in cells and is essential for the viability of eukaryotes. Human cells contain four HSP90 isotypes: cytosolic β-isotype constitutively expressed, inducible α-form, GRP94/gp96 in endoplasmic reticulum, and TRAP1/HSP75 in mitochondria. The α-form and β-form show 85% sequence homology
HSP90 is a key component of chaperoning structure, which catalyzes the folding of proteins referred to as HSP90 clients and control the quality thereof in normal cells and under stress conditions. The molecular chaperone activity, which is strictly dependent on the activity of adenosine triphosphatase, is closely modulated by the binding of other regulatory co-chaperones.
There is strong evidence that, in the case of, for example, cancer or other proliferative diseases, HSP90 becomes critical due to mutations or overexpression of particular oncogenes, or also due to tumors often having overloaded, misfolded proteins (which leads to an increased demand for the molecular chaperone function).
HSP90 is a homodimer consisting of three main domains in structure: a very conserved N-terminal domain, an intermediate domain of the triphosphatase adenylate domain and a C-terminal domain. N-terminal and C-terminal domains can bind to adenosine triphosphate. Most of the known inhibitors, such as geldanamycin, Radicicol, diarylpyrazole and purine derivatives, exhibit competitive binding to the N-terminal adenosine triphosphate binding site with adenosine triphosphate, while novobiocin is a prototype of an inhibitor that binds to the C-terminal pocket.
At present, HSP90 clients reported are increasing (Jolly et al., J. Natl. Cancer Inst. 92; 1564-1572(2000)), belonging to kinase family (Her2, B-RAF V600E, bcr-Abl, FIt3, NPM-ALK, Akt, Npm-Alk, ZAP-70), transcription factor (p53, HIF), telomerase and other molecular chaperones, most of which are closely related to the development of cancer. The ability of HSP90 to inhibit damaged folding or stabilize the client proteins thereof leads to protease-based degradation of these unfolded proteins. The degradation of these client proteins is often used as the indication of HSP90 inhibition, and the typical application is that in Her2 overexpressing cells, such as BT474 breast cancer cells, Her2 is degraded after treatment with compounds.
It has been shown that the natural compound geldanamycin can really block the proliferation of many tumor cells by the abilities of competitively binding to the N-terminal adenosine triphosphate binding site and inhibiting the activity of HSP90 adenosine triphosphatase, which initially caused a substantial amount of researches on the field of HSP90. Surprisingly, this compound is inactive in normal cells, and this may be because HSP90 is present in an active complex (with high affinity to geldanamycin) only existed in tumor cells (Kamal et al., Nature 425, 407-410 (2003)). Another possible reason for the selective sensitivity to tumors is tumor retention exhibited in many HSP90 inhibitors.
A large number of clinical evaluations are ongoing to tanespimycin (17-AAG), a semi-synthetic derivative of geldanamycin (GDA), and other related derivatives (alvespimycin, 17-DMAG, IPI-504), but the effects thereof appear to be limited by a number of factors: complex preparation, dependence on metabolism to produce active metabolites, lack of enrichment of patients, and hepatotoxicity possibly associated with quinone moiety. This leads to a large number of efforts to identify second-generation HSP90 inhibitors with better drug-likeness characters and better tolerability. This results in the identification of purine derivatives and aryl-resorcinol derivatives.
The main cause of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Prion disease, is that the accumulation of misfolded proteins leads to plaque formation. These misfolded proteins rely on molecular chaperones (HSP70, HSP40, etc.) for re-maturation, depolymerization and re-solubilization of protein aggregate. Heat shock protein has been shown to provide this function in a variety of cell culture models. HSF1 can induce HSP, and HSF1 is closely regulated by HSP90 in normal cells. It has been shown that HSP90 inhibitors, such as geldanamycin and 17-AAG derivatives, can disrupt this interaction and lead to HSP induction, resulting in neuroprotective activity as well as re-solubilization and depolymerization of misfolded proteins. HSP90 overexpression can significantly reduce the accumulation of misfolded proteins, and the accumulation of misfolded proteins is the cause of Alzheimer's disease. In fact, it has been shown that there is an inverse correlation between aggregated tau and HSP70/90 levels. Abnormal tau aggregation can be reduced by overexpression of HSP70, HSP27 and HSP40 (by degradation), which is triggered by inhibition of HSP90. Based on the in vivo effect of GDA on neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mouse models of Parkinson's disease, HSP90 inhibitors were used to treat Parkinson's disease. GDA protects neurons from MPTP-induced toxicity, which is closely related to elevated levels of HSP70. In addition, it has also been shown that HSP90 overexpression can significantly reduce the accumulation of misfolded proteins, which is the cause of motor injury, multiple sclerosis, spinal and bulbar muscular atrophy and other diseases.
GB1,406,345 disclosed a 4,6-disubstituted resorcinol compound having pharmacological activities. Other patent applications describe phenyl-heterocyclic compounds as HSP90 inhibitors, all of which are characterized by having a specific substitution mode of five-membered heterocycles, such as WO2006/101052 of Nippon Kayaku Kabushiki Kaisha; WO2005/000300, WO2004/072051 and WO2004/056782 of Vernalis; WO2003/055860 of Ribotargets; WO2008/097640 of Synta Pharmaceuticals; and WO2005/063222 of Kyowa Hakko Kogyo.
WO2004072051 relates to a class of HSP90 inhibitors, including Luminespib:

WO2006055760A1 reported some compounds, such as,

CN1771235A disclosed some compounds, such as,

These compounds are not desirable in terms of efficacy, pharmacokinetics, water solubility, druggability and the like.
Despite the above developments, there is still a need to develop more effective HSP90 inhibitors with low side effect.